Lactones

ABSTRACT

The present disclosure relates to novel lactones such as dihydropyrrole-fused furanones, a novel palladium-catalyzed carbonylation method to make the novel lactones, and method of using the novel lactones as anti-fungal and/or anti-bacteria agents.

CROSS-REFERENCE TO RELATED APPLICATION

The present U.S. patent application is related to and claims thepriority of U.S. Provisional Application Ser. No. 62/488,884, filed Apr.24, 2017, the contents of which are hereby incorporated by reference inits entirety into this application.

GOVERNMENT RIGHTS

This invention was made with government support under National ScienceFoundation Career Award No. 1553820 awarded by National ScienceFoundation. The United States government has certain rights in theinvention.

TECHNICAL FIELD

The present disclosure relates to novel lactones such asdihydropyrrole-fused furanones, a novel palladium-catalyzedcarbonylation method to make the novel lactones, and method of using thenovel lactones.

BACKGROUND

This section introduces aspects that may help facilitate a betterunderstanding of the disclosure. Accordingly, these statements are to beread in this light and are not to be understood as admissions about whatis or is not prior art.

Invasive fungal infections are a serious cause of mortality in manypatients including an increasing number of immunocompromised patients.Few treatment choices exist and first-line therapies have significantlimitations due to safety problem and lack of broad spectrum activity.

Novel antibacterial and antifungal agents and the efficient methods ofmaking the agents are therefore needed.

SUMMARY

The present invention provides compounds with novel structures that maypossess one or more of the following activities: antibacterial,antifungal, antiviral, anticancer, and antiparasitic activity.Specifically, the compounds of the present invention are represented inFormula I and Formula II below:

or any salt thereof, wherein either R¹-R⁷ are all hydrogen or at leastone of R¹-R⁷ is not hydrogen.

or any salt thereof, wherein either R¹-R⁹ are all hydrogen or at leastone of R¹-R⁹ is not hydrogen.

In one embodiment, the present disclosure provides palladium-catalyzedaminocarbonylative lactonization method of making compounds of Formula Iand/or Formula II.

In one embodiment, the present disclosure provides methods of usingcompounds of Formula I and/or Formula II as anti-bacterial and/oranti-fungal agents.

DETAILED DESCRIPTION

For the purposes of promoting an understanding of the principles of thepresent disclosure, reference will now be made to the embodimentsillustrated in the drawings, and specific language will be used todescribe the same. It will nevertheless be understood that no limitationof the scope of this disclosure is thereby intended.

In the present disclosure the term “about” can allow for a degree ofvariability in a value or range, for example, within 10%, within 5%, orwithin 1% of a stated value or of a stated limit of a range.

In the present disclosure the term “substantially” can allow for adegree of variability in a value or range, for example, within 90%,within 95%, or within 99% of a stated value or of a stated limit of arange.

The term “substituted” as used herein refers to a functional group inwhich one or more hydrogen atoms contained therein are replaced by oneor more non-hydrogen atoms. The term “functional group” or “substituent”as used herein refers to a group that can be or is substituted onto amolecule. Examples of substituents or functional groups include, but arenot limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom ingroups such as hydroxyl groups, alkoxy groups, aryloxy groups,aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups includingcarboxylic acids, carboxylates, and carboxylate esters; a sulfur atom ingroups such as thiol groups, alkyl and aryl sulfide groups, sulfoxidegroups, sulfone groups, sulfonyl groups, and sulfonamide groups; anitrogen atom in groups such as amines, azides, hydroxylamines, cyano,nitro groups, N-oxides, hydrazides, and enamines; and other heteroatomsin various other groups.

Non-limiting examples of substituents, that can be bonded to asubstituted carbon (or other such as nitrogen) atom include F, Cl, Br,I, OR, OC(O)N(R)₂, CN, NO, NO₂, ONO₂, azido, CF₃, OCF₃, R, O (oxo), S(thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)₂, SR, SOR,SO₂R, SO₂N(R)₂, SO₃R, (CH₂)₀₋₂P(O)OR₂, C(O)R, C(O)C(O)R, C(O)CH₂C(O)R,C(S)R, C(O)OR, OC(O)R, C(O)N(R)₂, OC(O)N(R)₂, C(S)N(R)₂,(CH₂)₀₋₂N(R)C(O)R, (CH₂)₀₋₂N(R)C(O)OR, (CH₂)₀₋₂N(R)N(R)₂, N(R)N(R)C(O)R,N(R)N(R)C(O)OR, N(R)N(R)CON(R)₂, N(R)SO₂R, N(R)SO₂N(R)₂, N(R)C(O)OR,N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)₂, N(R)C(S)N(R)₂, N(COR)COR, N(OR)R,C(═NH)N(R)₂, C(O)N(OR)R, or C(═NOR)R wherein R can be hydrogen or acarbon-based moiety, and wherein the carbon-based moiety can itself befurther substituted; for example, wherein R can be hydrogen, alkyl,acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, orheteroarylalkyl, wherein any alkyl, acyl, cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaryl, or heteroarylalkyl or R can be independentlymono- or multi-substituted; or wherein two R groups bonded to a nitrogenatom or to adjacent nitrogen atoms can together with the nitrogen atomor atoms form a heterocyclyl, which can be mono- or independentlymulti-substituted.

The term “aryl” as used herein refers to substituted or unsubstitutedcyclic aromatic hydrocarbons that do not contain heteroatoms in thering. Thus aryl groups include, but are not limited to, phenyl,azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl,triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl,anthracenyl, and naphthyl groups. In some embodiments, aryl groupscontain about 6 to about 14 carbons (C₆-C₁₄) or from 6 to 10 carbonatoms (C₆-C₁₀) in the ring portions of the groups. Aryl groups can beunsubstituted or substituted, as defined herein. Representativesubstituted aryl groups can be mono-substituted or substituted more thanonce, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substitutedphenyl or 2-8 substituted naphthyl groups, which can be substituted withcarbon or non-carbon groups such as those listed herein.

A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase“heterocyclyl group” includes fused ring species including those thatinclude fused aromatic and non-aromatic groups. Representativeheterocyclyl groups include, but are not limited to pyrrolidinyl,azetidinyl, piperidynyl, piperazinyl, morpholinyl, chromanyl,indolinonyl, isoindolinonyl, furanyl, pyrrolidinyl, pyridinyl,pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl,pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, triazyolyl, tetrazolyl,benzoxazolinyl, benzthiazolinyl, and benzimidazolinyl groups.

The terms “halo,” “halogen,” or “halide” group, as used herein, bythemselves or as part of another substituent, mean, unless otherwisestated, a fluorine, chlorine, bromine, or iodine atom. The compoundsdescribed herein may contain one or more chiral centers, or mayotherwise be capable of existing as multiple stereoisomers. It is to beunderstood that in one embodiment, the invention described herein is notlimited to any particular stereochemical requirement, and that thecompounds, and compositions, methods, uses, and medicaments that includethem may be optically pure, or may be any of a variety of stereoisomericmixtures, including racemic and other mixtures of enantiomers, othermixtures of diastereomers, and the like. It is also to be understoodthat such mixtures of stereoisomers may include a single stereochemicalconfiguration at one or more chiral centers, while including mixtures ofstereochemical configuration at one or more other chiral centers.

Similarly, the compounds described herein may include geometric centers,such as cis, trans, E, and Z double bonds. It is to be understood thatin another embodiment, the invention described herein is not limited toany particular geometric isomer requirement, and that the compounds, andcompositions, methods, uses, and medicaments that include them may bepure, or may be any of a variety of geometric isomer mixtures. It isalso to be understood that such mixtures of geometric isomers mayinclude a single configuration at one or more double bonds, whileincluding mixtures of geometry at one or more other double bonds.

The term “optionally substituted,” or “optional substituents,” as usedherein, means that the groups in question are either unsubstituted orsubstituted with one or more of the substituents specified. When thegroups in question are substituted with more than one substituent, thesubstituents may be the same or different. When using the terms“independently,” “independently are,” and “independently selected from”mean that the groups in question may be the same or different. Certainof the herein defined terms may occur more than once in the structure,and upon such occurrence each term shall be defined independently of theother.

As used herein, the term “salts” and/or “pharmaceutically acceptablesalts” refer to derivatives of the disclosed compounds wherein theparent compound is modified by making acid or base salts thereof.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic groups such asamines; and alkali or organic salts of acidic groups such as carboxylicacids. Pharmaceutically acceptable salts include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, and nitric; and the salts prepared from organic acids suchas acetic, propionic, succinic, glycolic, stearic, lactic, malic,tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

As used herein, the term “nitrogen-protecting group” in the presentdisclosure may be any functional group that can make the amine nitrogento be protected as any form of carbamate, benzyl amine, amide,thioamide, sulfonamide, urea, or thiourea. The nitrogen-protecting groupmay include but is not limited to benzoyl, benzyloxycarbonyl,t-butoxycarbonyl, benzene sulfonyl, toluene sulfonyl, benzyl,benzhydryl, trityl, acetyl, or trifluoroacetyl.

The present invention provides certain novel compounds that areanti-bacteria and/or anti-fungal agents. Accordingly, the presentinvention provides a compound of Formula I:

or any salt thereof, wherein either R¹-R⁷ are all hydrogen or at leastone of R¹-R⁷ is not hydrogen.

In one embodiment, the present invention provides a compound of FormulaI, wherein

R¹ is H, C1-C8 straight or branched alkyl, C3-C8 cycloalkyl, C6-C10aryl, C4-C10 heteroaryl, hydroxyl, C1-C6 straight or branched alkoxyl,—C(X)—R¹⁰, —C(X)—OR¹¹, —SO₂R¹², —C(X)NR¹³R¹⁴, or a nitrogen-protectinggroup, wherein the alkyl, aryl or heteroaryl is optionally substitutedwith one or more —NO₂, halogen, CF₃, or phenyl;

R², R³, R⁴, and R⁵ are independently H, C1-C8 straight or branchedalkyl, C3-C8 cycloalkyl, C6-C10 aryl, C4-C10 heteroaryl, hydroxyl,halogen, or C1-C6 straight or branched alkoxyl, wherein the alkyl, arylor heteroaryl is optionally substituted with one or more —NO₂, halogen,CF₃, or phenyl;

R⁶, R⁷ are independently H, C1-C8 straight or branched alkyl, C3-C8cycloalkyl, C6-C10 aryl, C4-C10 heteroaryl, C1-C6 straight or branchedalkoxyl, wherein R⁶, R⁷ may form a C3-C10 carbon ring or heterocyclicring comprising N, O, or S, and when the heterocyclic formed by R⁶ andR⁷ has N, the N is optionally attached to C1-C8 straight or branchedalkyl, C3-C8 cycloalkyl, C6-C10 aryl, C4-C10 heteroaryl, —C(X)—R¹⁰,—C(X)—OR¹¹, —SO₂R¹², —C(X)NR¹³R¹⁴, or a nitrogen-protecting group;

R¹-R¹⁴ are independently H, C1-C8 straight or branched alkyl, C3-C8cycloalkyl, C6-C10 aryl, C4-C10 heteroaryl, wherein the alkyl, aryl, orheteroaryl is optionally substituted with one or more C1-C4 straight orbranched alkyl, —NO₂, halogen, or CF₃; and

X is O or S.

In another embodiment, the present invention provides a compound ofFormula I wherein

R¹ is selected from the group consisting of H, C1-C4 straight orbranched alkyl, C3-C8 cycloalkyl, —C(O)—R¹⁰, —C(O)—OR¹¹, —SO₂R¹²,—C(O)NR¹³R¹⁴, and a nitrogen-protecting group, wherein the alkyl isoptionally substituted with one or more —NO₂, halogen, CF₃, or phenyl;

R², R³, R⁴, and R⁵ are independently selected from the group consistingof H, C1-C4 straight or branched alkyl, hydroxyl, halogen, and C1-C4straight or branched alkoxyl;

R⁶, R⁷ are independently selected from the group consisting of H, C1-C8straight or branched alkyl, C3-C8 cycloalkyl, C6-C10 aryl, C4-C10heteroaryl, C1-C6 straight or branched alkoxyl, wherein R⁶, R⁷ may forma C3-C10 carbon ring or heterocyclic ring comprising N, O, or S, andwhen the heterocyclic formed by R⁶ and R⁷ has N, the N is optionallyattached to C1-C4 straight or branched alkyl, C3-C8 cycloalkyl, C6-C10aryl, C4-C10 heteroaryl, —C(O)—R¹⁰, —C(O)—OR¹¹, —SO₂R¹², —C(O)NR¹³R¹⁴,and a nitrogen-protecting group; and

R¹⁰-R¹⁴ are independently H, C1-C4 straight or branched alkyl, C3-C8cycloalkyl, C6-C10 aryl, C4-C10 heteroaryl, wherein the alkyl, aryl, orheteroaryl is optionally substituted with one or more C1-C4 straight orbranched alkyl, —NO₂, halogen, or CF₃.

In one embodiment, the present invention provides a compound of FormulaII:

or any salt thereof, wherein either R¹-R⁹ are all hydrogen or at leastone of R¹-R⁹ is not hydrogen.

In one embodiment, the present invention provides a compound of FormulaII, wherein

R¹ is H, C1-C8 straight or branched alkyl, C3-C8 cycloalkyl, C6-C10aryl, C4-C10 heteroaryl, hydroxyl, C1-C6 straight or branched alkoxyl,—C(X)—R¹⁰, —C(X)—OR¹¹, —SO₂R¹², —C(X)NR¹³R¹⁴, or a nitrogen-protectinggroup, wherein the alkyl, aryl or heteroaryl is optionally substitutedwith one or more —NO₂, halogen, CF₃, or phenyl;

R², R³, R⁴, R⁵, R⁶, and R⁷ are independently H, C1-C8 straight orbranched alkyl, C3-C8 cycloalkyl, C6-C10 aryl, C4-C10 heteroaryl,hydroxyl, halogen, or C1-C6 straight or branched alkoxyl, wherein thealkyl, aryl or heteroaryl is optionally substituted with one or more—NO₂, halogen, CF₃, or phenyl;

R⁸, R⁹ are independently H, C1-C8 straight or branched alkyl, C3-C8cycloalkyl, C6-C10 aryl, C4-C10 heteroaryl, C1-C6 straight or branchedalkoxyl, wherein R⁸, R⁹ may form a C3-C10 mono or bicyclic carbon ringor heterocyclic ring comprising N, O, or S, and when the heterocyclicformed by R⁸ and R⁹ has N, the N is optionally attached to C1-C8straight or branched alkyl, C3-C8 cycloalkyl, C6-C10 aryl, C4-C10heteroaryl, or a nitrogen-protecting group;

R¹⁰-R¹⁴ are independently H, C1-C8 straight or branched alkyl, C3-C8cycloalkyl, C6-C10 aryl, C4-C10 heteroaryl, wherein the alkyl, aryl orheteroaryl is optionally substituted with one or more C1-C4 straight orbranched alkyl, —NO₂, halogen, or CF₃, and

X is O or S.

In another embodiment, the present invention provides a compound ofFormula II, wherein

R¹ is selected from the group consisting of H, C1-C4 straight orbranched alkyl, C3-C8 cycloalkyl, —C(O)—R¹⁰, —C(O)—OR¹¹, —SO₂R¹²,—C(O)NR¹³R¹⁴, and a nitrogen-protecting group, wherein the alkyl isoptionally substituted with one or more —NO₂, halogen, CF₃, or phenyl;

R²-R⁷ are independently selected from the group consisting of H, C1-C4straight or branched alkyl, hydroxyl, halogen, and C1-C4 straight orbranched alkoxyl;

R⁸, R⁹ are independently selected from the group consisting of H, C1-C8straight or branched alkyl, C3-C8 cycloalkyl, C6-C10 aryl, C4-C10heteroaryl, C1-C6 straight or branched alkoxyl, wherein R⁸, R⁹ may forma C3-C10 carbon ring or heterocyclic ring comprising N, O, or S, andwhen the heterocyclic formed by R⁸ and R⁹ has N, the N is optionallyattached to C1-C4 straight or branched alkyl, C3-C8 cycloalkyl, C6-C10aryl, C4-C10 heteroaryl, —C(O)—R¹⁰, —C(O)—OR¹¹, —SO₂R¹², —C(O)NR¹³R¹⁴,and a nitrogen-protecting group; and

R¹⁰-R¹⁴ are independently H, C1-C4 straight or branched alkyl, C3-C8cycloalkyl, C6-C10 aryl, C4-C10 heteroaryl, wherein the alkyl, aryl, orheteroaryl is optionally substituted with one or more C1-C4 straight orbranched alkyl, —NO₂, halogen, or CF₃.

In one embodiment, the present invention provides a compound selectedfrom the group consisting of:

In one embodiment, the present invention provides a compound selectedfrom the group consisting of:

In one embodiment, the present invention provides a compound of FormulaI as an anti-fungal and/or anti-bacteria agent.

In one embodiment, the present invention provides a compound of FormulaII as an anti-fungal and/or anti-bacteria agent.

In one embodiment, the present invention provides a compound of FormulaI as an inhibitor for Clostridium difficile.

In one embodiment, the present invention provides a compound of FormulaI as an inhibitor for Clostridium difficile P8, Clostridium difficileBAA1870, Clostridium difficile P 20, Clostridium difficile P 7,Clostridium difficile P 21, or any combination thereof.

In one embodiment, the present invention provides a compound of FormulaI as an inhibitor of strains of Candida albicans, Candida glabrata,Candida krusei, Cryptococcus gattii, Cryptococcus neoformans,Aspergillus fumigatus, Aspergillus niger, Aspergillus brasiliensis, orany combination thereof.

In one embodiment, the present invention provides a compound of FormulaII as an inhibitor of strains of Candida albicans, Candida glabrata,Candida krusei, Cryptococcus gattii, Cryptococcus neoformans,Aspergillus fumigatus, Aspergillus niger, Aspergillus brasiliensis, orany combination thereof.

In one embodiment, the present invention provides a method of making thecompound of Formula I in any embodiment of the present disclosure,wherein the method comprises reacting a compound of formula A withcarbon monoxide, a palladium catalyst, a ligand, and an oxidant in asolvent to provide the compound of formula I:

wherein R¹-R¹⁴ are defined in any embodiment for compound of formula I.

In one embodiment, the present invention provides a method of making thecompound of Formula II in any embodiment of the present disclosure,wherein the method comprises reacting a compound of formula B withcarbon monoxide, a palladium catalyst, a ligand, and an oxidant in asolvent to provide the compound of Formula II:

wherein R¹-R¹⁴ are defined in any embodiment for compound of Formula II.

The compounds of the present invention may be prepared by a variety ofprocedures, some of which are illustrated in the schemes below. Somesubstituents may be eliminated in the following schemes for the sake ofclarity and are not intended to limit the teaching of the schemes in anyway.

The method of preparing the compound of Formula I is illustrated inScheme 1.

Compound A is reacted with carbon monoxide with a suitable palladiumcatalyst such as Pd(tfa)2 [palladium(II) trifluoroacetate], a suitableligand such as 2,2-bipyridine, and a suitable oxidant such asp-benzoquinone, in a suitable solvent such as acetonitrile (MeCN) at asuitable temperature such as room temperature to provide the compound ofFormula (I).

The method of preparing the compound of Formula II is illustrated inScheme 2.

The reaction condition to prepare the compound of Formula II isessentially the same or similar to the preparation of the compound ofFormula I except a different starting material with the Formula B isused. It was expected to achieve a fused six-membered ring to afive-membered ring based on the product of Formula I. However, thecompound of Formula II is obtained as a novel scaffold which does nothave a fused bicyclic rung system. Instead, a two-ring connected througha double bond is unexpectedly obtained.

The method of preparing the compound A and compound B are illustrated inScheme 3 and Scheme 4.

Compound C and D (Scheme 3) or E and F (Scheme 4) are reacted with asuitable base such as n-BuLi in a suitable solvent such astetrahydrofuran (THF) to provide compound A or compound B. Compounds C,D, E and F are either commercial available or may be made by the methodsknown to skilled artisans.

The ligands that may be suitable for the reactions as disclosed in thepresent disclosure may include but is not limited to:

The oxidants that may be suitable for the reactions as disclosed in thepresent disclosure may include but is not limited to p-benzoquinone and2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

General Methods:

NMR spectra were recorded on Bruker spectrometers (¹H at 500 MHz and ¹³Cat 125 MHz). Chemical shifts (δ) were given in ppm with reference tosolvent signals [¹H NMR: CHCl₃ (7.26); ¹³C NMR: CDCl₃ (77.2)]. Columnchromatography was performed on silica gel. All reactions sensitive toair or moisture were conducted under argon atmosphere in dry and freshlydistilled solvents under anhydrous conditions, unless otherwise noted.Anhydrous THF was distilled over sodium benzophenone ketyl under Argon.Anhydrous CH₂Cl₂ was distilled over calcium hydride under Argon.Anhydrous MeCN was distilled over calcium hydride under Argon. All othersolvents and reagents were used as obtained from commercial sourceswithout further purification.

Preparations Preparation 1:N-(5-hydroxy-7-phenylhept-3-yn-1-yl)-4-methylbenzenesulfonamide

To a stirred solution of N-(but-3-yn-1-yl)-4-methylbenzenesulfonamide(112 mg, 0.50 mmol) in dry THF (5 mL), a 2.5 M solution of n-BuLi (0.39mL, 0.98 mmol) in hexane was added dropwise at −78° C. over 10 min underargon atmosphere. The reaction mixture was allowed to react at the sametemperature and stirred for a 1 h. Dissolved 3-phenylpropanal (1.5 mmol)in 5 mL THF and added at −78° C. over 10 min to the previously formedmixture. The formed mixture was allowed to warmed up to room temperatureand react for additional 1 h. The reaction was quenched by saturatedNH₄Cl solution (5 mL) and extracted by EtOAc for 3 times. The organiclayer was washed with brine, dried over Na₂SO₄ and concentrated underreduced pressure. The resulting residue was purified by flashchromatography (hexane/ethyl acetate=3/2) to provide Preparation 1 in64% yield. HRMS (ESI), calcd for C₂₀H₂₃NO₃SNa [M+Na]⁺380.1297, found380.1280 m/z.

TABLE 1 Preparations 2-22 are prepared with essentially the same orsimilar method of preparing Preparation 1. Physical Data [HRMS (ESI):m/z)] Preparations Structures Chemical names [M + Na]⁺  2

N-(5-hydroxyoct-3-yn-1-yl)-4- methylbenzenesulfonamide 318.1094  3

N-(5-hydroxy-6-phenylhex-3-yn- 1-yl)-4- methylbenzenesulfonamide352.1004  4

N-(5-(4-fluorophenyl)-5- hydroxypent-3-yn-1-yl)-4-methylbenzenesulfonamide 370.0929  5

N-(5-hydroxy-5-(4- (trifluoromethyl)phenyl)pent-3- yn-1-yl)-4-methylbenzenesulfonamide 420.0786  6

N-(5-(3-bromophenyl)-5- hydroxypent-3-yn-1-yl)-4-methylbenzenesulfonamide 430.0099  7

N-(5-hydroxy-5-(naphthalen-1- yl)pent-3-yn-1-yl)-4-methylbenzenesulfonamide 402.1066  8

N-(5-hydroxy-5-phenylpent-3-yn- 1-yl)-4- methylbenzenesulfonamide366.1105  9

N-(4-(1-hydroxycycloheptyl)but- 3-yn-1-yl)-4- methylbenzenesulfonamide358.1405 10

N-(4-(4-hydroxytetrahydro-2H- pyran-4-yl)but-3-yn-1-yl)-4-methylbenzenesulfonamide 346.1049 11

N-(4-(1-hydroxycyclopentyl)but- 3-yn-1-yl)-4- methylbenzenesulfonamide330.1099 12

N-(4-(1-hydroxycyclohexyl)but-3- yn-1-yl)-4- methylbenzenesulfonamide344.1228 13

N-(5-hydroxy-5-methylhex-3- yn-1-yl)-4- methylbenzenesulfonamide304.0950 14

N-(5-hydroxy-5,5-diphenylpent-3- yn-1-yl)-4- methylbenzenesulfonamide428.1320 15

N-(4-(1-hydroxycyclobutyl)but- 3-yn-1-yl)-4- methylbenzenesulfonamide314.0950 16

N-(4-(3-hydroxyoxetan-3-yl)but- 3-yn-1-yl)-4- methylbenzenesulfonamide318.0752 17

tert-butyl 3-hydroxy-3-(4-((4- methylphenyl)sulfonamido)but-1-yn-1-yl)azetidine-1-carboxylate 417.1402  18*

N-(5-hydroxy-6,6-dimethylhept-3- yn-1-yl)-4- methylbenzenesulfonamide332.1272  19*

N-(5-hydroxy-5-(4- nitrophenyl)pent-3-yn-1-yl)-4-methylbenzenesulfonamide 397.0816  20*

N-(5-hydroxypent-3-yn-1-yl)-4- methylbenzenesulfonamide 276.0623 21

tert-butyl (5-hydroxy-7- phenylhept-3-yn-1-yl)carbamate 326.1717 22

N-(6-hydroxy-8-phenyloct-4-yn- 1-yl)-4- methylbenzenesulfonamide394.1378 23

N-(6-hydroxynon-4-yn-1-yl)-4- methylbenzenesulfonamide 332.1211 *ThePreparations 18-20 are made from Boc-protected starting material andthen treated with trifluoroacetic acid (TFA) to de-protect to providethe desired compounds.

EXAMPLES PREPARED BY PALLADIUM-CATALYZED CARBONYLATION Example 1:6-phenethyl-1-tosyl-1,2,3,6-tetrahydro-4H-furo[3,4-b]pyrrol-4-one

Add Pd(MeCN)₂C12 (2.6 mg, 0.01 mmol), AgOTf (5.2 mg, 0.02 mmol) andligand G (3.6 mg, 0.01 mmol) in dry MeCN (2 mL) and allowed to react for1 h under argon atmosphere. Then add DDQ (34.1 mg, 0.15 mmol) andPreparation 1, which isN-(5-hydroxy-7-phenylhept-3-yn-1-yl)-4-methylbenzenesulfonamide (0.1mmol), to the mixture, and the reaction was filled by CO balloon. Themixture was allowed to react at room temperature and the reaction wasmonitored by Thin Layer Chromatography (TLC) until no starting materialwas observed. The solvent was removed under reduced pressure and theresidue was dissolved in CHCl₃ (1 mL). The crude product in CHCl₃ waspurified by flash column chromatography (CHCl₃ then hexane/ethylacetate=5/1) to give Example 1 in 90% yield. HRMS (ESI) [M+H]⁺: 384.1308m/z.

TABLE 2 Examples 2-23 are prepared with essentially the same or similarmethod of preparing Example 1. Physical Data [HRMS (ESI): ExamplesStructures Chemical names m/z)] [M + H]⁺  2

6-propyl-1-tosyl-1,2,3,6-tetrahydro- 4H-furo[3,4-b]pyrrol-4-one 322.1165 3

6-(tert-butyl)-1-tosyl-1,2,3,6- tetrahydro-4H-furo[3,4-b]pyrrol-4- one336.1257  4

6-benzyl-1-tosyl-1,2,3,6-tetrahydro- 4H-furo[3,4-b]pyrrol-4-one 370.1098 5

6-(4-nitrophenyl)-1-tosyl-1,2,3,6- tetrahydro-4H-furo[3,4-b]pyrrol-4-one 401.0790  6

6-(4-fluorophenyl)-1-tosyl-1,2,3,6- tetrahydro-4H-furo[3,4-b]pyrrol-4-one 374.0913  7

1-tosyl-6-(4- (trifluoromethyl)phenyl)-1,2,3,6-tetrahydro-4H-furo[3,4-b]pyrrol-4- one 424.0872  8

6-(3-bromophenyl)-1-tosyl-1,2,3,6- tetrahydro-4H-furo[3,4-b]pyrrol-4-one 424.0040  9

6-(naphthalen-1-yl)-1-tosyl-1,2,3,6- tetrahydro-4H-furo[3,4-b]pyrrol-4-one 406.1110 10

6-phenyl-1-tosyl-1,2,3,6-tetrahydro- 4H-furo[3,4-b]pyrrol-4-one 356.096311

1-tosyl-1,2,3,6-tetrahydro-4H- furo[3,4-b]pyrrol-4-one 280.0612 12

1′-tosyl-2′,3′- dihydrospiro[cycloheptane-1,6′-furo[3,4-b]pyrrol]-4′(1′H)-one 362.1399 13

1-tosyl-2,2′,3,3′,5′,6′- hexahydrospiro[furo[3,4-b]pyrrole-6,4′-pyran]-4(1H)-one 350.1029 14

1′-tosyl-2′,3′- dihydrospiro[cyclopentane-1,6′-furo[3,4-b]pyrrol]-4′(1′H)-one 334.1082 15

1′-tosyl-2′,3′- dihydrospiro[cyclohexane-1,6′-furo[3,4-b]pyrrol]-4′(1′H)-one 348.1230 16

6,6-dimethyl-1-tosyl-1,2,3,6- tetrahydro-4H-furo[3,4-b]pyrrol-4- one308.0969 17

6,6-diphenyl-1-tosyl-1,2,3,6- tetrahydro-4H-furo[3,4-b]pyrrol-4- one432.1238 18

1′-tosyl-2′,3′- dihydrospiro[cyclobutane-1,6′-furo[3,4-b]pyrrol]-4′(1′H)-one 320.0955 19

1-tosyl-2,3-dihydrospiro[furo[3,4- b]pyrrole-6,3′-oxetan]-4(1H)-one322.0743 20

tert-butyl 4′-oxo-1′-tosyl-1′,2′,3′,4′- tetrahydrospiro[azetidine-3,6′-furo[3,4-b]pyrrole]-1-carboxylate 431.1374 21

(E)-4-phenethyl-3-(1- tosylpyrrolidin-2-ylidene)oxetan-2- one 398.135622

(E)-4-propyl-3-(1-tosylpyrrolidin-2- ylidene)oxetan-2-one 336.1236

Biological Evaluation

The broth microdilution assay was utilized to determine the minimuminhibitory concentration (MIC) of the Examples in the present disclosureagainst certain bacterial (Methicillin-resistant Staphylococcus aureus(MRSA), Enterococcus faecium, Acinetobacter baumannii, Escherichia coli,Klebsiella pneumoniae, Pseudomonas aeruginosa and Clostridium difficile)and fungal pathogens (Candida albicans, Candida glabrata, Candidakrusei, Cryptococcus gattii, Cryptococcus neoformans, Aspergillusfumigatus, Aspergillus niger, and Aspergillus brasiliensis) followingthe guidelines of the Clinical and Laboratory Standards Institute.

Minimum Inhibitory Concentrations (MICs) Against C. difficile Strains

Clostridium difficile was grown anaerobically on brain heart infusionsupplemented agar plates (Brain heart infusion medium, BD, supplementedwith yeast extract, L-cysteine, Vitamin K1 and Hemin, Sigma) at 37° C.for 48 hours, afterwards a bacterial solution equivalent to 0.5McFarland standard was prepared in PBS and diluted in brain heartinfusion supplemented broth to achieve a bacterial concentration ofabout 5×10⁵. Drugs were added at a concentration of 128 μM in the firstrow of a 96-well plates, 100 μL of the bacterial suspension was added toall the wells of the plates and two-fold serial dilution was done foreach compound. See Institute CaLS. 2012. Methods for DilutionAntimicrobial Susceptibility Tests for Bacteria That GrowAerobically—Ninth Edition: Approved Standard M07-A9, Wayne, Pa. Plateswere then incubated at 37° C. anaerobically for 48 hours and examinedfor turbidity, MIC is considered the lowest concentration of a compoundthat can inhibit the development of visual turbidity.

Cytotoxicity Against Human Colorectal Adenocarcinoma Cell Line (Caco-2)

Examples were assayed at concentrations of 32, 64, 128, and 256 μMagainst human colorectal cancer-derived intestinal epithelial cell line(Caco-2) to determine the potential toxic effect on mammalian cells.About ×10⁴ cells suspended in 100 μL of DMEM media (supplemented with10% fetal bovine serum and 1% non-essential amino acids) were seeded ina 96-well plate and incubated at 37° C. in a 5% CO₂ atmosphere. Afterreaching confluency, cells were further incubated with the abovementioned concentrations of the compounds for 2 hours. The culture mediawere discarded, and the cells in each well were washed with media and100 μL of cell culture media were added prior to addition of the assayreagent MTS3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)(Promega). The plates were incubated for 4 hours at 37° C. in humidified5% CO₂ atmosphere. The absorbance at 490 nm was recorded and correctedabsorbance readings (actual absorbance readings for each treatmentsubtracted from background absorbance) were taken using a kinetic ELISAmicroplate reader (SpectraMax i3x, Molecular Devices, Sunnyvale, Calif.,USA). The quantity of viable cells after treatment with each compoundwas expressed as a percentage of the control, DMSO. Statistical analysiswas performed using two way ANOVA followed by Dunnett's pairwisecomparison (P<0.05).

Antifungal Assay

Yeast and mold fungal suspensions were prepared and tested by brothmicrodilution method according to the guidelines of Clinical andLaboratory Standards Institute. See (CLSI) Clsi. 04/2008. Referencemethod for broth dilution antifungal susceptibility testing of yeast;approved standards-third edition (M27-A3). 28.

Compounds (tested from 128 μM down to 1 μM) were placed together in a 96well-plate and incubated at 35° C. for 24 to 72 hours according to thestrain tested. The MICs reported represent the lowest concentration ofeach compound necessary to inhibit bacterial growth

Antibacterial Activities

Examples 8 and 19 exhibited promising inhibitory activities of 64 μM to128 μM minimum inhibitory concentrations (MIC) against toxigenic strainssuch as C. difficile P8, C. difficile BAA1870, C. difficile P 20, C.difficile P 7, and C. difficile P 21.

In addition, the toxicity study of Examples 8 and 19 against Caco-2 cellline demonstrated that neither compound showed toxicity up to 256 μM.

Antifungal Activities

Examples 8, 11, 19, and 22 exhibited promising inhibitory activitiesagainst certain fungal pathogens including strains of Candida albicans,Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcusneoformans, Aspergillus fumigatus, Aspergillus niger, and Aspergillusbrasiliensis with 64 μM to 128 μM minimum inhibitory concentrations.

Those skilled in the art will recognize that numerous modifications canbe made to the specific implementations described above. Theimplementations should not be limited to the particular limitationsdescribed. Other implementations may be possible.

We claim:
 1. A compound of formula (I)

or any salt thereof, wherein R¹ is H, C1-C8 straight or branched alkyl,C3-C8 cycloalkyl, C6-C10 aryl, C4-C10 heteroaryl, hydroxyl, C1-C6straight or branched alkoxyl, —C(X)—R¹⁰, —C(X)—OR¹¹, —SO₂R¹²,—C(X)NR¹³R¹⁴, or a nitrogen-protecting group, wherein the alkyl, aryl orheteroaryl is optionally substituted with one or more —NO₂, halogen,CF₃, or phenyl; R², R³, R⁴, and R⁵ are independently H, C1-C8 straightor branched alkyl, C3-C8 cycloalkyl, C6-C10 aryl, C4-C10 heteroaryl,hydroxyl, halogen, or C1-C6 straight or branched alkoxyl, wherein thealkyl, aryl or heteroaryl is optionally substituted with one or more—NO₂, halogen, CF₃, or phenyl; R⁶, R⁷ are independently H, C1-C8straight or branched alkyl, C3-C8 cycloalkyl, C6-C10 aryl, C4-C10heteroaryl, C1-C6 straight or branched alkoxyl, wherein R⁶, R⁷ may forma C3-C10 carbon ring or heterocyclic ring comprising N, O, or S, andwhen the heterocyclic formed by R⁶ and R⁷ has N, the N is optionallyattached to C1-C8 straight or branched alkyl, C3-C8 cycloalkyl, C6-C10aryl, C4-C10 heteroaryl, —C(X)—R¹⁰, —C(X)—OR¹¹, —SO₂R¹², —C(X)NR¹³R¹⁴,or a nitrogen-protecting group; R¹⁰-R¹⁴ are independently H, C1-C8straight or branched alkyl, C3-C8 cycloalkyl, C6-C10 aryl, C4-C10heteroaryl, wherein the alkyl, aryl, or heteroaryl is optionallysubstituted with one or more C1-C4 straight or branched alkyl, —NO₂,halogen, or CF₃; and X is O or S.
 2. The compound of claim 1, whereinthe compound is made by a method comprises reacting a compound offormula A with carbon monoxide, a palladium catalyst, a ligand, and anoxidant in a solvent to provide the compound of formula I:


3. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


4. The compound of claim 1, wherein the compound is used as ananti-bacteria or anti-fungal agent.
 5. A method of preparing thecompound of formula (I) of claim 1, wherein the method comprisesreacting a compound of formula A with carbon monoxide, a palladiumcatalyst, a ligand, and an oxidant in a solvent to provide the compoundof formula I:

R¹ is H, C1-C8 straight or branched alkyl, C3-C8 cycloalkyl, C6-C10aryl, C4-C10 heteroaryl, hydroxyl, C1-C6 straight or branched alkoxyl,—C(X)—R¹⁰, —C(X)—OR¹¹, —SO₂R¹², —C(X)NR¹³R¹⁴, or a nitrogen-protectinggroup, wherein the alkyl, aryl or heteroaryl is optionally substitutedwith one or more —NO₂, halogen, CF₃, or phenyl; R², R³, R⁴, and R⁵ areindependently H, C1-C8 straight or branched alkyl, C3-C8 cycloalkyl,C6-C10 aryl, C4-C10 heteroaryl, hydroxyl, halogen, or C1-C6 straight orbranched alkoxyl, wherein the alkyl, aryl or heteroaryl is optionallysubstituted with one or more —NO₂, halogen, CF₃, or phenyl; R⁶, R⁷ areindependently H, C1-C8 straight or branched alkyl, C3-C8 cycloalkyl,C6-C10 aryl, C4-C10 heteroaryl, C1-C6 straight or branched alkoxyl,wherein R⁶, R⁷ may form a C3-C10 carbon ring or heterocyclic ringcomprising N, O, or S, and when the heterocyclic formed by R⁶ and R⁷ hasN, the N is optionally attached to C1-C8 straight or branched alkyl,C3-C8 cycloalkyl, C6-C10 aryl, C4-C10 heteroaryl, —C(X)—R¹⁰, —C(X)—OR¹¹,—SO₂R¹², —C(X)NR¹³R¹⁴, or a nitrogen-protecting group; R¹⁰-R¹⁴ areindependently H, C1-C8 straight or branched alkyl, C3-C8 cycloalkyl,C6-C10 aryl, C4-C10 heteroaryl, wherein the alkyl, aryl, or heteroarylis optionally substituted with one or more C1-C4 straight or branchedalkyl, —NO₃, halogen, or CF₃; and X is O or S.